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PubMed2004

Growth hormone protects the intestines but not the tumour from 5-fluorouracil toxicity in the short term in the rat.

OBJECTIVE: Growth hormone has been proposed as an effective preventative treatment against radiotherapy- and chemotherapy-induced toxicity in the gut. The aim of this study was to determine whether exogenously administered growth hormone modified the effect of 5-fluorouracil on the gut and an implanted colon adenocarcinoma in the rat METHODS: An adenocarcinoma was implanted into rats that had been treated with 5-fluorouracil and growth hormone 3 days previously. Tumour growth, plus tumour and intestinal pathology, proliferation, apoptosis and p53 expression were determined. RESULTS: Growth hormone protected the intestines against 5-fluorouracil by increasing proliferation and mucosal length, and decreasing apoptosis and p53 expression. Growth hormone did not modify the effects of 5-fluorouracil on the tumour. CONCLUSIONS: Growth hormone protects the intestines from the deleterious effects of 5-fluorouracil while preserving its antitumoural action on the adenocarcinoma in the short term. Within the crypt, p53 expression is likely to be modulated by growth hormone after 5-fluorouracil treatment.

Adenocarcinoma↗
PubMed2001

Single intraoperative application of 5-Fluorouracil versus placebo in low-risk trabeculectomy surgery: a randomized trial.

PURPOSE: Trabeculectomy is the procedure of choice for the surgical control of glaucoma, and is often augmented by intraoperative 5-fluorouracil application to reduce scarring. This study aims to assess the validity of this technique with a randomized placebo-controlled trial. METHODS: Patients without risk factors for bleb failure other than previous drop use who were undergoing trabeculectomy surgery as their first ocular procedure were randomized to receive fluorouracil or placebo. The main outcome measures were intraocular pressure and bleb morphology. RESULTS: Results from 40 eyes of 36 patients are presented; 23 eyes were treated with fluorouracil, and 17 eyes were treated with placebo. Mean intraocular pressure at 1 year and at the final follow-up examination was significantly lower than preoperatively, but was not different between fluorouracil and placebo groups. Kaplan-Meier survival analysis also failed to show any difference, though there was a trend toward better survival of an intraocular pressure of 16 mm Hg or lower. Bleb morphology was examined postoperatively in 24 patients, with no differences found between fluorouracil and placebo groups. CONCLUSIONS: No significant difference was found in trabeculectomy outcome between fluorouracil-treated and placebo-treated eyes. The study was too small to state definitively that no such difference exists, but suggests that any treatment effect is likely to be small.

Aged↗
PubMed2005

5-fluorouracil selectively inhibits collagen synthesis.

BACKGROUND: Fibroproliferative disorders, such as Dupuytren's contracture of the hand, are characterized by excessive production of collagen. 5-Fluorouracil has been used to treat fibroproliferative disorders of the eye and skin and is thought to inhibit thymidylate synthetase blocking DNA replication. 5-Fluorouracil has been shown to down-regulate fibroblast proliferation and differentiation in vitro. METHODS: This study investigated the dose-dependent effect of 5-fluorouracil on fibroblast extracellular matrix production. Fibroblasts were derived from tendon and primary Dupuytren's disease of the hand, a fibroproliferative disorder of the palmar aponeurosis (n = 4 patients). Total collagen synthesis was determined by means of the incorporation of radiolabeled proline. Fibroblast secretion of the profibrotic factor transforming growth factor-beta1 (TGF-beta1) was measured by a sandwich enzyme-linked immunosorbent assay. Gene expression of collagen types I and III and TGF-beta1 were quantified by means of reverse-transcriptase polymerase chain reaction assays. RESULTS: The authors found that 5-fluorouracil caused a dose-dependent, selective, and specific decrease in collagen production by Dupuytren's fibroblasts compared with noncollagenous protein synthesis. By contrast, procollagen types I and III mRNA were unaffected by 5-fluorouracil treatment. These changes did not appear to be mediated by alterations in the endogenous secretion of TGF-beta1 or its autocrine effect on collagen metabolism. CONCLUSIONS: The clinical implication is that 5-fluorouracil could possibly reduce extracellular matrix production and therefore reduce recurrence of Dupuytren's disease of the hand.

Antimetabolites↗
PubMed1986

Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora.

The mechanism of toxicity from 5-fluorocytosine chemotherapy is unclear. However, recent evidence suggests that the generation of 5-fluorouracil by a host may play an important role in the development of this toxicity. Using an in vitro semicontinuous culture system to mimic the intestinal microflora, we examined the capacity of this complex microbial community to convert 5-fluorocytosine to 5-fluorouracil. The system was dosed initially and after 2 weeks of chronic exposure to 5-fluorocytosine with radiolabeled 5-fluorocytosine. No detectable production of 5-fluorouracil was observed up to 8 h after the acute dose; however, at 24 h and at all time points thereafter, increasing levels of 5-fluorouracil were detected for 4 days. The chronic dose resulted in an increased rate of 5-fluorouracil production without the 8-h lag time. These findings suggest that the enzyme or enzymes responsible for the deamination of 5-fluorocytosine to 5-fluorouracil by the intestinal microflora can be induced by chronic exposure to 5-fluorocytosine and that this conversion may provide a mechanism through which 5-fluorocytosine toxicity is manifested.

Bacteria↗
PubMed1980

Incorporation and excision of 5-fluorouracil from deoxyribonucleic acid in Escherichia coli.

When Escherichia coli are grown in the presence of 5-fluorouracil, the 5-fluorouracil is incorporated almost exclusively into ribonucleic acid as fluorouridylate. In this study, small but detectable amounts were incorporated into ribonucleic acid as fluorocytidylate and into deoxyribonucleic acid as fluorodeoxyuridylate and fluorodeoxycytidylate. The amount of 5-fluorouracil found in deoxyribonucleic acid as fluorodeoxyuridylate increased 50-fold when the cells were deficient in both deoxyuridine triphosphatase and uracil-deoxyribonucleic acid glycosylase activities. Therefore, the same mechanisms which excluded uracil from deoxyribonucleic acid in vivo also excluded 5-fluorouracil. Even though purified uracil-deoxyribonucleic acid glycosylase excised 5-fluorouracil from deoxyribonucleic acid at only 5% the rate with which it excised uracil, most of the 5-fluorouracil excised from deoxyribonucleic acid in vivo was apparently excised directly by uracil-deoxyribonucleic acid glycosylase rather than by repair initiated by excision of uracil.

DNA Glycosylases↗
PubMed1994

Fluorouracil cardiotoxicity.

OBJECTIVE: To review the clinical manifestations, postulated mechanisms, and therapeutic implications of fluorouracil-induced cardiac toxicity. DATA SOURCE: A MEDLINE search was used to identify pertinent literature. STUDY SELECTION: Studies and case reports on fluorouracil cardiotoxicity were identified through a MEDLINE search. A manual review of bibliographies of identified articles was performed to ensure that all pertinent articles were included. DATA EXTRACTION: Data pertaining to all aspects of fluorouracil cardiac toxicity, including pathogenesis, predisposing factors, clinical manifestations, and therapeutic implications, were evaluated. DATA SYNTHESIS: Estimates from large series suggest a 1.6-2.3 percent incidence of clinically demonstrated cardiotoxicity. Predisposing factors include the presence of coronary artery disease and concurrent radiotherapy. Postulated mechanisms include direct myocardial ischemia, coronary spasm, or cardiotoxic impurities in fluorouracil formulation. Clinical manifestations include chest pain, nausea, diaphoresis with typical ischemic electrocardiographic (ECG) changes, relieved to normal after stopping the drug therapy. Nitrates and calcium-channel blockers do not protect against cardiotoxicity. CONCLUSIONS: Fluorouracil cardiotoxicity may be much more common and clinically significant than previously thought. A high index of suspicion for cardiotoxicity must be maintained when the drug is administered, especially in the presence of heart disease and concomitant radiation therapy. In the presence of chest pain, it is mandatory to stop the infusion and, if possible, to replace fluorouracil with another chemotherapeutic agent.

Chest Pain↗
PubMed1997

Rapid loss of fentanyl citrate admixed with fluorouracil in polyvinyl chloride containers.

OBJECTIVE: To study the physical compatibility and chemical stability of fluorouracil 1 and 16 mg/mL with fentanyl citrate 12.5 micrograms/mL in dextrose 5% and in sodium chloride 0.9% injection. DESIGN: Test solutions of the drugs in dextrose 5% injection and in sodium chloride 0.9% injection were prepared in triplicate and stored at -20, 4, 23, and 32 degrees C. Samples were removed immediately and at various times over 7 days and stored at -70 degrees C until analyzed. Physical compatibility was assessed visually and by measuring turbidity with a color-correcting turbidimeter; particle content was measured with a light-obscuration particle sizer and counter. Chemical stability was determined by measuring the concentration of each drug in the test solutions in duplicate with stability-indicating HPLC. RESULTS: Fentanyl citrate was rapidly lost when admixed with fluorouracil in polyvinyl chloride (PVC) containers, losing about 25% in the first 15 minutes and about 50% in the first hour. The loss of fentanyl citrate was so rapid that accurate time zero determinations were not possible. The extent of fentanyl loss increased with time and occurred more rapidly at the higher temperatures (i.e., 23, 32 degrees C). Losses of 70% or more occurred in all samples within 24 hours. Fentanyl underwent rapid sorption to the containers at the high pH (9.0-9.5) of the fluorouracil admixtures. Adjusting the pH of a fentanyl citrate solution (containing no fluorouracil) in PVC containers to pH 9 with sodium hydroxide also resulted in rapid sorption loss. Fentanyl citrate sorption did not occur when admixtures were prepared in polyethylene containers. Fluorouracil remained stable for at least 7 days at all temperatures. There were no visual or subvisual changes in turbidity or particle content in any of the test solutions at any time. CONCLUSIONS: When admixed with fluorouracil 1 and 16 mg/mL in dextrose 5% injection and sodium chloride 0.9% injection, fentanyl citrate 12.5 micrograms/mL underwent rapid and extensive loss due to sorption to the PVC containers, making the combination unacceptable within minutes of mixing. The sorption results from the alkaline pH of the admixture and, presumably, could occur from the admixture of fentanyl citrate with any sufficiently alkaline drug.

Analgesics, Opioid↗
PubMed2000

Effects of pegylated recombinant human megakaryocyte growth and development factor on 5-fluorouracil-induced thrombocytopenia in balloon-injured rats.

We examined whether pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) affected 5-fluorouracil-induced thrombocytopenia without inducing more severe intimal thickening after injury to rat carotid arteries. Rat carotid arteries were injured using a balloon catheter on day 0. 5-Fluorouracil (100 mg kg(-1)) or vehicle was intravenously administered on day 1 in balloon-injured rats. PEG-rHuMGDF (100 microg kg(-1)) or vehicle was intravenously administered once a day on days 1-5 to balloon-injured rats given 5-fluorouracil or vehicle. 5-Fluorouracil (100 mg kg(-1), i.v.) caused a significant decrease in the platelet count from day 3 and peaked on days 7-9 in balloon-injured rats. PEG-rHuMGDF (100 microg kg(-1), i.v.) reduced this decrease on days 9 and 11. The administration of PEG-rHuMGDF did not accelerate the intimal thickening of balloon-injured arteries in rats treated with 5-fluorouracil compared with control balloon-injured rats. PEG-rHuMGDF did not increase plasma tumour growth factor-beta1 (TGF-beta1) from days 0-9 in balloon-injured rats compared with control balloon-injured rats. These results suggest that PEG-rHuMGDF ameliorated 5-fluorouracil-induced thrombocytopenia without accelerating the intimal thickening of balloon-injured arteries.

Animals↗
PubMed1980

Isolation and characterization of the murine lymphoma L5178Y cell line highly resistant to 5-fluorouracil.

5-Fluorouracil-resistant cell line designated as L5178Y/FU was established in this experiment. This is one of the colonies derived from the subculture which acquired resistance to 5-fluorouracil by passing the L5178Y cells through ten successive episodes of culture in Fischer's medium containing 5-fluorouracil, in which each 5-fluorouracil treatment was followed by recovery intervals. The resistance of this line is about 80-fold that of the IC99 of 5-fluorouracil, and also shows a cross resistance to both 5-fluorouridine and 5-fluoro-2'-deoxyuridine. 5-Fluoro-2'-deoxyuridine resistant subline designated as L5178Y/FUdR was also isolated from the subculture which acquired resistance to 5-fluoro-2'-deoxyuridine by using the same selection procedure. The resistance of this line is about 650-fold that of the IC99 of 5-fluoro-2'-deoxyuridine, and shows a partial cross-resistance to 5-fluorouridine, but not to 5-fluorouracil.

Animals↗
PubMed2000

Fluorouracil-induced neurotoxicity.

OBJECTIVE: To report a case of acute neurologic adverse effects related to fluorouracil administration and to review the neurotoxicity of this agent. CASE SUMMARY: A 73-year-old white man with a history of esophageal carcinoma was treated with fluorouracil 1,500 mg iv daily for four days. After completing treatment, he presented with sudden onset of confusion, cognitive disturbances, a cerebellar syndrome, and repeated seizures. A magnetic resonance image of the brain showed no structural abnormalities, and cerebrospinal fluid examination was normal; none of the other laboratory tests provided an explanation for his symptoms. The patient was treated with anticonvulsants, and the cognitive changes resolved in 72 hours. The cerebellar signs, however, did not resolve completely and persisted when the patient was examined two weeks after discharge. DISCUSSION: Fluorouracil can cause both acute and delayed neurotoxicity. Acute neurotoxicity manifests as encephalopathy or as cerebellar syndrome; seizures, as seen in our patient, have rarely been reported. Acute neurotoxicity due to fluorouracil is dose related and generally self-limiting. Various mechanisms for such toxicity have been postulated, and treatment with thiamine has been recommended. Delayed neurotoxicity has been reported when fluorouracil was given in combination with levamisole; this form of subacute multifocal leukoencephalopathy is immune mediated and responds to treatment with corticosteroids. CONCLUSIONS: Clinicians should be aware of the adverse neurologic effects of fluorouracil and should include them in the differential diagnosis when patients receiving the drug present with neurologic problems.

Aged↗
PubMed1999

[Experimental study on intraperitoneal administration of 5-fluorouracil for liver metastasis in comparison with intravenous administration].

We studied the effects of 5-fluorouracil intraperitoneal administration using mouse liver metastasis model. We inoculated 50 microliters Colon26 cell suspension into the spleen and resected it 15 min after cell inoculation under general anesthesia with Ketamine. Control group (n = 7) had no treatment. The intraperitoneal (i.p.) group (n = 8) and intravenous (i.v.) group (n = 7) underwent the treatment on the 2nd and 4th day after the operation. Experimental chemotherapies consisted of 1.5 ml 5-fluorouracil solution (50 mg/kg) for i.p. group and 0.2 ml 5-fluorouracil solution (50 mg/kg) for i.v. group. On the 14th day after the cell implantation, necropsies were performed. Deposits on mouse livers were counted and the mouse livers weighted. Counting of metastatic liver deposits revealed the number of deposits in the control group was 25.6 +/- 12.9, against 2.9 +/- 1.9 and 16.0 +/- 15.6, in the i.p. and i.v. group, respectively. Significant differences in the number of liver deposits were obtained between the control group and i.p. group, and between i.p. group and i.v. group (p < 0.05). The mean liver weight (mg)/mouse body weight (g) were 76.3 +/- 24.7 in the control group, 54.3 +/- 4.7 in the i.p. group and 60.0 +/- 12.7 in the i.v. group. A significant difference was observed only between the control group and the i.p. group (p < 0.05). I.p. administration of 5-fluorouracil was superior to i.v. administration for control of the liver metastasis. Moreover, the side effect by 5-fluorouracil i.p. treatment was milder than by i.v. therapy. We confirmed the effectiveness of 5-fluorouracil intraperitoneal chemotherapy for the potential liver metastasis and liver micrometastasis. Intraperitoneal chemotherapy is also useful for peritoneal seeding. We think intraperitoneal chemotherapy is a recommendable administration route for gastrointestinal malignancies.

Animals↗
PubMedDate not supplied

The effect of preoperative 5-fluorouracil on colonic healing: an experimental study.

BACKGROUND/AIMS: After curative resection for colorectal carcinoma there is a high recurrence rate and neoadjuvant chemotherapy may be useful in some patients. Very little is known about the effect of preoperative 5-fluorouracil on the healing of colon anastomosis. The aim of this study was to evaluate the effect of 5-fluorouracil on colonic healing when the time interval between the last injection and operation was shortened to 24 hours. METHODOLOGY: Thirty-six male Wistar rats with a median weight of 185 g (range: 165-200 g) were divided into three groups: 1) control group (n = 12); 2) sham group (n = 12) which received saline intraperitoneally, and 3) study group (n = 12) which received 5-fluorouracil intraperitoneally (20 mg/kg-1). All injections were given intraperitoneally for 5 days and the last dose was injected 24 hours before operation. RESULTS: The mortality rate (22.7%) and anastomotic complications (29.4%) were increased in the 5-fluorouracil group, compared with the control or saline groups (P < 0.05). The anastomotic bursting pressure in rats having 5-fluorouracil treatment (27 mm Hg) was significantly lower from both the control (55 mm Hg) and saline (84 mm Hg) groups on postoperative day 3 (P < 0.05). Both myeloperoxidase and hydroxyproline contents were also significantly lower than the other groups (P < 0.05). CONCLUSIONS: Colonic healing was impaired and mortality rate was increased when intraperitoneal 5-fluorouracil treatment was repeated until 24 hours before operation.

Anastomosis, Surgical↗
PubMedDate not supplied

Antineoplastic effect of orally administered 1-alkyl carbamoyl derivatives of 5-fluorouracil on sc implanted Lewis lung carcinoma and B16 melanoma.

The antitumor activity of 1-alkyl carbamoyl derivatives of 5-fluorouracil against Lewis lung carcinoma and B16 melanoma by long-term oral administration was examined. The 1-hexyl and 1-phenethyl carbamoyl-5-fluorouracil derviatives were markedly active against early Lewis lung carcinoma among the derivatives tested. These compounds were not markedly active against advanced Lewis lung carcinoma but did show acceptable activity. Increases in lifespan in mice with early Lewis lung carcinoma at optimal doses of 1-hexyl and 1-phenethyl carbamoxyl-5-fluorouracil were 98% and 78% respectively. In advanced Lewis lung carcinoma, the 1-hexyl derivative was active by either intermittent or daily administration, but the 1-phenethyl derivative was active only by daily administration. Lung metastases were not inhibited by optimal doses of the 1-hexyl derivative but were completely inhibited by the 1-phenethyl derivative. The 1-hexyl derivative was also active against B16 melanoma and the increase in lifespan at optimal doses was 27%. As a result, 1-hexyl carbamoyl-5-fluorouracil was found to be the most active derivative against early Lewis lung carcinoma and B16 melanoma. However, 1-phenethyl carbamoyl-5-fluorouracil was the most active derivative against advanced Lewis lung carcinoma by daily administration and this compound completely inhibited lung metastases, while 5-fluorouracil and cyclophosphamide did not inhibit lung metastases.

Administration, Oral↗
PubMed1975

The effect of 5-fluorouracil on the mitotic cycle and DNA synthesis in the epithelium of mouse small intestine.

The examinations were performed on 42 mice of the Porton strain. The experimental animals were injected intraperitoneally with the dose of 75 mg of 5-fluorouracil per kg body weight. The first experimental group received injections of [3H]thymidine within 48 hours and the second group within 96 hours of the injection of 5-fluorouracil. Two mice from each group were killed at within 1, 2, 4, 8, 12, 24, and 48 hours of the [3H]thymidine injection. Calculations of the mitotic index and time of duration of individual phases of the mitotic cycle in epithelial cells of the small intestine were based on application of the autoradiographic method. These studies lead to the conclusion that 5-fluorouracil disturbs the course of metabolic processes in the cell, which are also related with the distribution of the genetic material. Histological examinations show that 5-fluorouracil produces profound morphological changes in the intestine, which affect both the intestinal epithelium and the connective tissue stroma. The autoradiographic tests revealed a considerable suppression of the mitotic activity of the epithelium of intestinal crypts. Moreover, it was shown that 5-fluorouracil inhibits the mitotic activity of the intestinal epithelium by diminishing the number of cells capable of entering into mitosis. Nevertheless, by 96 hours following introduction of a single dose of 5-fluorouracil normal morphological structure and mitotic activity of the intestinal wall cells are restored.

Animals↗
PubMed2002

Pemetrexed disodium combined with oxaliplatin, SN38, or 5-fluorouracil, based on the quantitation of drug interactions in human HT29 colon cancer cells.

Premetrexed disodium (MTA) is a novel multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. It exhibits a broad spectrum of activity against several human tumor types including colorectal cancer. Therefore, we evaluated the anti-proliferative potential of MTA combined with drugs known to exert therapeutic activity against colon cancer, including 5-fluorouracil, oxaliplatin, and SN38, the active metabolite of irinotecan. The effects of MTA, alone or combined with one of theses 3 drugs, were investigated in parental human HT29 colon cancer cells and in 5-fluorouracil-resistant counterparts HT29-5FU cells. These drugs were administered either simultaneously or sequentially. Functional interactions between MTA, 5-fluorouracil, oxaliplatin, and SN38 were evaluated using median-effect plot analysis. The drug combination and sequence with optimal effects were evaluated in athymic mice bearing human HT29 tumor cell xenografts. Combinations of MTA with 5-fluorouracil required high concentrations to achieved additive and/or synergistic effects. Simultaneous exposure to MTA and oxaliplatin led to synergistic activity in both parental and 5-fluorouracil-resistant human HT29 colon cancer cells, leading to additive antitumor effects and minimal toxicity in athymic mice bearing HT29 cell tumors. Synergism between MTA and SN38 was also observed in both parental and 5-fluorouracil-resistant HT29 cells. These results argue in favor of clinical trials of chemotherapy combining MTA with oxaliplatin or irinotecan (CPT-11), for the treatment of patients with colon cancer.

Animals↗
PubMed2002

[Pharmacokinetic study of postoperative peritoneal infusion with large bulk heated hypotonic 5-fluorouracil fluid for prevention of recurrence and hepatic metastasis of gastric cancer].

BACKGROUND & OBJECTIVE: At present, only few animal experiment has been reported about the pharmacokinetic of peritoneal chemotherapy. The aim of this study was to determine the pharmacokinetic change following large bulk heated hypotonic 5-fluorouracil fluid perfusing into peritoneal immediately after radical resection. METHODS: (1) Fifty patients with gastric cancer after radical resection were randomly assigned into ten groups. They were given intraperitoneal infusion of warm (43 degrees C-45 degrees C) distilled water (1,250 ml/m2) plus 5-fluorouracil (500 mg/L) after radical gastrectomy. At various time intervals (0, 0.08, 0.25, 0.5, 0.75, 1, 3, 6, 12, 24 h), blood samples from the femoral artery and vein, portal vein, and peritoneal fluid were collected. (2) 25 cases of patients with gastric cancer were randomized into five groups, each group also included 5 cases. They were also given intraperitoneal infusion at 1, 3, 6, 12, 24 h with the same fluid before operation, blood samples from portal vein were drawn at the beginning of operation. (3) 5-fluorouracil concentration of above all of samples were determined by high performance liquid chromatography (HPLC). RESULTS: (1) The peak concentration of peritoneal fluid, portal vein, femoral artery and vein were at 0, 0.08, 1.00, 1.00 h, respectively, after peritoneal infusion. (2) The peak and average concentration in peritoneal fluid were 167.7-fold and 180.4-fold as high as that of the femoral vein respectively. (3) The peak and average concentration in portal vein were 5.4-fold and 6.7-fold as high as that of the femoral vein respectively. (4) The concentration changes of 5-fruorouracil in peritoneal fluid, portal vein, femoral artery and vein were all suitable for two compartment open model. The pharmacokinetics parameters of above all the fluid were in turn: AUC0-->tn(mg.L-1.h) 3667.36, 143.82, 31.02, 26.84; alpha(h-1) 1.1076, 0.6269, 7.7923, 21.5643; beta(h-1) 0.0367, 0.0474, 0.2091, 0.2014; CL(L.h-1) 0.16, 4.92, 35.36, 39.32; T1/2 alpha(h) 0.62, 1.11, 0.09, 0.03; T1/2 beta(h) 18.88, 14.64, 3.31, 3.44; (5) The portal vein 5-fluorouracil concentration at various times were all lower than that of the preoperation, suggesting that 5-fluorouracil can pass through retroperitoneal spaces into systemic circulation. CONCLUSION: Postoperative large bulk heated hypotonic fluid peritoneal infusion with 5-fluorouracil has pharmacokinetic characteristic of high selective regional chemotherapy providing higher and lasting concentration in peritoneal fluid and portal vein. Therefore, this method should be a more reasonable chemotherapy for the prevention of recurrence and liver metastasis of gastric cancer after radical resection.

Antimetabolites, Antineoplastic↗
PubMed2005

Chemotherapy of metastatic colorectal cancer: fluorouracil plus folinic acid and irinotecan or oxaliplatin.

(1) Following the recent introduction of several new cytotoxic agents, a new look at the role of chemotherapy in metastatic colorectal cancer is needed. (2) In one clinical trial of first-line treatment, fluorouracil + folinic acid infusion, after an initial bolus (LV-5FU2 protocol), was more effective and better tolerated than bolus administration alone (Mayo Clinic protocol). (3) Five comparative trials failed to show that raltitrexed was more effective than fluorouracil + folinic acid in first-line treatment, and it has more serious adverse effects. (4) There are no comparative trials of capecitabine or tegafur + uracil versus fluorouracil + folinic acid (LV-5FU2 protocol) in first-line treatment. (5) In three comparative randomised trials involving previously untreated patients, adjunction of oxaliplatin to the fluorouracil + folinic acid combination (FOLFOX protocol) increased both tumour response rate and progression-free survival (by about 2 months), but it also caused more neuropathies, severe diarrhea and severe neutropenia. (6) In two comparative trials of first-line treatment, adjunction of irinotecan to fluorouracil + folinic acid (FOLFIRI protocol) increased the median survival time by about 3 months, to 15-17 months, but increased the incidence of diarrhea, neutropenia, serious cardiovascular disorders and severe thrombosis. (7) In second-line treatment, irinotecan is the only properly assessed drug with a positive impact, prolonging survival compared with appropriate palliative care (34 months after diagnosis, versus 27 months). (8) In one comparative trial, first-line treatment with the FOLFOX protocol, followed by the FOLFIRI protocol, resulted in the same median survival time (21 months) as the reverse sequence. (9) In practice, the first-line treatment for metastatic colorectal cancer appears to be the fluorouracil + folinic acid combination (LV-5FU2 protocol) plus either oxaliplatin (FOLFOX protocol) or irinotecan (FOLFIRI protocol). The reference second-line treatment is the FOLFIRI protocol (or the FOLFOX protocol if the FOLFIRI protocol has already been used). These treatments were associated with the longest survival in one trial.

Antibodies, Monoclonal↗
PubMed2006

[Synthesis of 5-fluorouracil derivatives containing alkanoic acid].

OBJECTIVE: To synthesize 5-fluorouracil derivatives containing 2-5 carbon alkanoic acid. METHODS: N1-substituted derivatives containing alkanoic acid were prepared through the hydrolysis of these products of the reaction of haloesters and excessive amount of 5-fluorouracil. 5-fluorouracil were protected with tertbutoxycarbonyl (Boc) at N1-position, then reacted with haloesters and deprotected in turn, through this "one-pot" method, N3-substituted 5-FU alkanoic acid esters can be obtained, with high yields (75%-85%). The hydrolysis of these products gave N3-substituted 5-FU alkanoic acid at last. RESULTS: Including 10 new compounds and 8 aim compounds, 16 derivatives of 5-fluorouracil were obtained and confirmed by the spectral detection. CONCLUSIONS: The reaction of excessive amount of 5-fluorouracil and haloesters can produce a good yield of N1-substituted derivatives. N3-substituted derivatives can be obtained through the reactions of 5-fluorouracil protected with Boc at N1-position and haloesters.

Alkanes↗